Neuropeptide Y (NPY) is a 36 amino acid peptide present in high concentration in mammalian brain. Injection of NPY into hypothalamic regions elicits a powerful feeding response in rats, and NPY has been strongly implicated in diabetes and obesity. The peripheral satiety factor, leptin, has been shown to exert a satiety stimuli in mice and rats by inhibiting the synthesis and release of NPY in hypothalamic sites that are known to regulate eating behavior. Most importantly, PYY 3-36, a peripheral homologue of NPY released from the L-cells of the gut into the circulation after a meal, is reported to act as a satiety signal. Administration of PYY 3-36 in humans significantly decreased appetite and attenuated food intake by 33 percent for up to 24 hours. Recent surveys show that obesity in USA has increased from 17.9 percent in 1998 to 18.9 percent in 1999, and a sharp increase in diabetes is expected. Excess body weight and obesity also increase the risk of other problems such as hypercholesterolemia and heart disease. In an attempt to understand the causes of eating disorders and obesity, we propose to elucidate the molecular mechanisms regulating NPY-induced feeding in the hypothalamus. Activation of Y1 and Y5 receptors of NPY in the hypothalamic PVN by NPY trigger the hunger signal by inhibiting cAMP accumulation and mobilizing intracellular Ca++. These two prominent second messengers activate a transcription factor, CREB, the activation of which regulates many CREB-dependent genes. These biochemical events translate into a hunger signal. PYY 3-36 activates hypothalamic Y2 receptors to turn off the hunger stimuli. Our long-term goal is to investigate the signal transduction cascade and the regulatory genes involved in maintaining energy homeostasis. In ,the present research proposal we will investigate three specific aims:l) To determine whether the changes in the circulating hormones that regulate feeding behavior alter hypothlamic cAMP/PKA and phosphoCREB activities, 2) To investigate whether the food-induced release of gut peptide PYY 3-36 blunts the activity of CREB to elicit a satiety signal, and 3) To determine whether Y1 and Y5 receptor subtypes act through the inhibition of cAMP and stimulation of CREB signaling system. These findings are critical to understanding the molecular bases of obesity development and to develop a treatment plan.